Alzheimer's disease displays the deposition of two aberrant proteins: 2-amyloid plaques (A2) and neurofibrially tangles (NFT). Neurofibrillary tangles consist of hyperphosphorylated tau protein and are found within the neuron. Recently it has been found that a specific kinase, cyclin-dependent kinase-5 (CDK5), when activated by the cyclin p25 hyperphosphorylates tau and results in the deposition of the paired helical filaments that comprise neurofibrillary tangles. An increasing body of evidence indicates that p25/CDK5 may play a central neruotoxic role in Alzheimer's disease. Our long-term goals are two-fold. First, to develop small-molecule inhibitors of the neuro-toxic events contributing to Alzheimer's disease. Second to establish the practical utility of selectively inhibiting a multi-unit enzyme complex formed uniquely at the nexus of a disease process. Our central hypothesis is that potent conformationally constrained inhibitors can selectively inhibit the p25/CDK5 complex, reduce tau hyperphosphorylation, NFT deposition, and reduce neurodegeneration in Alzheimer's disease. We plan to test our central hypothesis and accomplish the central objective of this application by pursing these two specific aims: Specific Aim 1: Synthesize potent flexible inhibitors of p25/CDK5. Specific Aim 2: Synthesize potent conformationally constrained inhibitors to selectively inhibit p25/CDK5 versus p35/CDK5. PUBLIC HEALTH RELEVANCE As the baby-boomer population reaches retirement, over 10 million Americans are likely to develop Alzheimer's disease unless a cure is found. We know that two types of protein are central to the disease process: amyloid plaques (A2) and neurofibrillary tangles (NFT's). We hope that by preventing NFT formation, we can help America preserve its memory and recognize its future. [unreadable] [unreadable] [unreadable]